Abstract 3004: Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with nintedanib on human colorectal cancer xenografts

Abstract

Abstract Background: TAS-102 (also named TFTD) is a novel antitumor nucleoside. This is a combination of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and tipiracil hydrochloride (TPI) at a molar ratio 1:0.5. FTD is the active antitumor component of TAS-102 and its triphosphate form is incorporated into DNA in tumor cells. TPI is an inhibitor of thymidine phosphorylase, which strongly inhibits the biodegradation of FTD. In a recent global, multicenter, randomized, double-blind Phase III study (RECOURSE), TAS-102 showed to significantly improve overall survival and progression-free survival and had a favorable safety profile in comparison to those achieved with placebo in patients with metastatic colorectal cancer refractory to standard chemotherapies. Nintedanib is an oral triple angiokinase inhibitor that simultaneously inhibits vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and fibroblast growth factor receptors. It is currently being investigated in Phase III studies of advanced non-small cell lung cancer, colorectal cancer, and ovarian cancer. In this study, we evaluated the antitumor effects of TAS-102 in combination with nintedanib on human colorectal tumor xenografts in a nude mouse model. Method: Drug cytotoxicity was determined by the crystal violet staining method using DLD-1, HT-29, and HCT116 colorectal cancer cell lines. Drug interaction was evaluated by performing isobologram analysis. Furthermore, the human colorectal cancer cell lines were implanted into nude mice subcutaneously, and TAS-102 (150 mg/kg/day) and/or nintedanib (20 or 40 mg/kg/day) were orally administered twice daily from Days 1 to 14. Growth inhibitory activity was evaluated based on tumor volume. Results: The combination of TAS-102 and nintedanib exerted an additive effect on growth inhibition of DLD-1 and HT-29, and a sub-additive effect on HCT116 in vitro. TAS-102 and nintedanib monotherapies were both active on all of the evaluated colorectal cancers in vivo. Tumor growth inhibition by combination therapy (150 mg/kg/day TAS-102 plus 40 mg/kg/day nintedanib) was 61.5%, 67.6%, and 67.5% for DLD-1, HT-29, and HCT116 xenografts, and that was significantly superior to that of either monotherapy for all evaluated cancer xenografts (P < 0.05). These results demonstrate that combination therapy with TAS-102 and nintedanib is significantly more effective than either monotherapy in colorectal cancer xenografts. This combination therapy appeared to be well tolerated because neither a reduction in body weight of more than 20% nor drug-related death was observed. Conclusion: Combination therapy of TAS-102 and nintedanib is significantly more effective than either monotherapy in preclinical models and should be considered for investigation in metastatic colorectal cancer patients. Citation Format: Norihiko Suzuki, Fumio Nakagawa, Mamoru Nukatsuka, Kazuaki Matsuoka, Hiroshi Tsukihara, Teiji Takechi. Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with nintedanib on human colorectal cancer xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3004.